Some viruses, especially HIV, must undergo a complex process called fusion in order to enter the host cell and reproduce. During fusion, the outer membrane of the virus fuses with the membrane of the host cell. In the case of HIV, the outer membrane of the HIV virus fuses with the membrane of the CD4+ T cell during reproduction.
T20 is a member of a new class of antiviral agents that inhibit virus/membrane fusion. In the case of HIV, this provides two salutary effects: the reproduction of HIV is blocked and resultant death of the CD4+ T cells does not occur.
Data from two large, internationally conducted Phase III trials indicate that combination therapy with T-20 reduced HIV to undetectable levels in the blood in at least twice the percentage of patients and provided an improved immune response at 24 weeks, as compared to those who took combination therapy without T-20. Additionally, those receiving T-20 were less likely to experience virological failure or relapse over 24 weeks.
In the first Phase III trial, conducted in North America and Brazil, 37 percent of patients who were treated with T-20 in combination with an optimized background regimen had undetectable blood levels (less than 400 copies/mL) of HIV at 24 weeks, compared to 16 percent who received an optimized background regimen alone (p<0.0001). Combination therapy with T-20 further reduced HIV viral load to less than 50 copies/mL in 20 percent of patients as compared to 7 percent who took combination therapy alone (P=0.0002).
The primary efficacy endpoint for the study, the mean difference in the magnitude of decrease in HIV between the two groups in the study, was 0.934 log 10 copies/mL (p<0.0001). Patients who received T-20 as part of their combination regimen achieved a reduction in HIV levels of 1.697 1 log10 copies/mL, compared to 0.763 log 10 copies/mL for those in the control arm. Furthermore, 52 percent of patients receiving T-20 experienced a 1.0 log10 or greater reduction in HIV levels, compared to 29 percent who did not receive T-20 (P<0.0001). Patients in the T-20 arm experienced a mean CD4+ cell increase of 76 cells/mm3, as compared to 32 cells/mm3 in the control arm (p<0.0001).
Results from the second Phase III clinical trial, conducted in Europe and Australia, were consistent with findings from the first study. 28 percent of patients who were treated with T-20 in combination with an optimized background regimen had undetectable blood levels (less than 400 copies/mL) of HIV at 24 weeks, compared to 14 percent receiving an optimized background regimen alone (p<0.0001). Combination therapy with T-20 further reduced HIV viral load to less than 50 copies/mL in 12 percent of patients as compared to 5 percent who took combination therapy alone (P=0.0099).
The mean difference in the magnitude of decrease in HIV between the two arms at 24 weeks was 0.78 log 10 copies/mL (p<0.0001). Patients who received T-20 as part of their combination regimen achieved a mean reduction in HIV levels of 1.43 log 10 copies/mL, compared to a mean of 0.65 log 10 copies/mL for those in control arm. Furthermore, 43 percent of patients receiving T-20 experienced a 1.0 log 10 or greater reduction in HIV levels, compared to 21 percent who did not receive T-20 (P<0.0001). Patients in the T-20 arm experienced a mean CD4+ cell increase of 65 cells/mm3, as compared to 38 cells/mm3 in the control arm (p=0.023).
At entry, an optimized background regimen (consisting of three to five drugs, including up to two newly approved or investigational drugs, if appropriate) was chosen for each patient based on treatment history and antiretroviral resistance testing. After selection of the regimen, patients were randomized 2:1 to receive either the regimen in combination with T-20 or the regimen alone. Patients randomized to T-20 received T-20 administered as one 90 mg subcutaneous self-injection twice-daily.
Viral resistance to currently approved anti-HIV drugs is a significant issue in the clinical management of HIV today. Many patients who begin combination antiretroviral treatment with currently approved medications will develop resistance to one or more of these agents over time. Research suggests, however, that T20 may be unaffected by resistance to any of the currently approved antiretroviral classes. (Data presented at the 5th International Workshop on Drug Resistance and Treatment Strategies in Scottsdale, Ariz., Jun. 4–8, 2001). Additional experiments show that the in vitro activity of T20 is not affected by mutations associated with resistance to reverse transcriptase inhibitors and protease inhibitors.
Like many polypeptide therapeutic agents, T20 is generally administered by injection. Current therapeutic protocols often involve more than one daily injection.
It would, therefore, be advantageous to provide T20 polypeptides and pharmaceutical compositions having improved performance and pharmacokinetic characteristics. It would be particularly advantageous to provide for lower therapeutic doses of T20, less frequent administrations, and/or extended duration of action.
These and other objects of the present invention are described in greater detail below.